Dr. Lebowitz is currently conducting research in the laboratory of John P. Johnson at the Univeristy of Pittsburgh. His career goals for the period of this grant are to further develop both the technical expertise (e.g. in molecular, biochemical, and electrophysiological methods) and in the creative skills necessary to become a successful independent investigator. After 1-2 years of mentored research he plans to make the transition to a tenure-track faculty position within the renal division. His long term goal is to become a fully independent academic investigator performing basic research in an environment where bench results may be applied to important clinical problems within the broad fields of nephrology and cellular physiology. He is especially interested in the regulation of epithelial transport systems. The basis for this research project is a the discovery of a novel interaction between the beta subunit of the kinase that cleaves the inhibitor of nuclear factor kappa B (IKKbeta) and the beta subunit of the epithelial sodium channel (ENaC). Using the yeast two hybrid system and immunoprecipitation techniques, we have established this interaction. Further, using the two electrode voltage clamping technique and co-expression of IKKbeta and all three ENaC subunits in Xenopus oocytes, we have shown that this interaction increases ENaC activity. Although studies have linked activation of nuclear factor kappa B (NF-kappaB) with changes in ENaC activity, no study has elucidated the nature of this relationship nor has any research explored the basic mechanism involved. Since our results show that ENaC may be activated through the NF-kappaB cascade as well as regulated by glucocorticoids and mineralocorticoids, an interaction between these two pathways is apparent. Preliminary data demonstrates that mineralocorticoids may also activate pathways in renal and pulmonary epithelia.